The primary source of nutrients for the body is blood, which is composed of highly functional proteins including immunoglobulin, albumin, fibrinogen and hemoglobin. Immunoglobulins are products of mature B cells (plasma cells) and there are five distinct immunoglobulins referred to as classes: M, D, E, A, and G. IgG is the main immunoglobulin class in blood. Intravenous administration of immunoglobulin products has long been used to attempt to regulate or enhance the immune system. Most evidence regarding the effects of intravenous IgG on the immune system suggests the constant fraction (Fc) portion of the molecule plays a regulatory function. The specific antigen binding properties of an individual IgG molecule are conferred by a three dimensional steric arrangement inherent in the amino acid sequences of the variable regions of two light and two heavy chains of the molecule. The constant region can be separated from the variable region if the intact molecule is cleaved by a proteolytic enzyme such as papain. Such treatment yields two fractions with antibody specificity (Fab fractions) and one relatively constant fraction (Fc).
sIgA is the predominant immunoglobulin class secreted onto mucosal surfaces through body fluids such as saliva, tears, milk, bronchoalveolar fluid, and other secretions. IgA has previously been shown to possess anti-inflammatory characteristics. See e.g. Wolf H M, et al. (1994), Human serum IgA downregulates the release of inflammatory cytokines (tumor necrosis factor-alpha, Interleukin-6) in human monocytes, Blood 83:1278-1288. In contrast, the same authors did not demonstrate the anti-inflammatory effects for an IgG-containing composition. IgA does not exist in concentrations in blood or milk to facilitate sufficient concentration for oral administration. In addition, immunoglobulin of any class is to large of a molecule to permit absorption to achieve therapeutic effects after oral administration. Oral immunoglobulin has been shown to be beneficial for treatment of gastrointestinal disease and other gastrointestinal conditions but neither anti-infective nor anti-inflammatory effects have been demonstrated in pulmonary tissue. Thus, the fact that IgA is anti-inflammatory does not allow it to be used as a suitable treatment of pulmonary inflammation.
Numerous cells in the body have distinct membrane receptors for the Fc portion of an IgG molecule (Fcr). Although some Fcr receptors bind free IgG, most bind it more efficiently if an antigen is bound to the antibody molecule. Binding an antigen results in a configurational change in the Fc region that facilitates binding to the receptor. A complex interplay of signals provides balance and appropriateness to an immune response generated at any given time in response to an antigen. Antigen specific responses are initiated when specialized antigen presenting cells introduce antigen, forming a complex with the major histocompatibility complex molecules to the receptors of a specific helper inducer T-cells capable of recognizing that complex. IgG appears to be involved in the regulation of both allergic and autoimmune reactions. Intravenous immunoglobulin for immune manipulation has long been proposed but has achieved mixed results in treatment of disease states. A detailed review of the use of intravenous immunoglobulin as drug therapy for manipulating the immune system is described in Vol. 326, No. 2, pages 107-116, New England Journal of Medicine Dwyer, John M., the disclosure of which is hereby incorporated by reference.
Lipopolysaccharide (LPS), also commonly referred to as endotoxin, a major proinflammatory glycolipid component of the gram-negative bacterial cell wall, is one of the agents ubiquitously present as contaminant on airborne particles, including air pollution, organic dusts, and cigarette smoke. Chronic exposure to significant levels of LPS is reported to be associated with the development and/or progression of many types of lung diseases, including asthma, chronic bronchitis, and progressive irreversible airflow obstruction, that are all characterized by chronic inflammatory processes in the lung.
There is a continuing effort and need in the art for improved compositions and methods for reducing the effects of LPS and other inflammatory components in the lungs that do not require higher levels of IgA. It is therefore an object of the present invention to provide methods and pharmaceutical compositions for treating animals with pulmonary immune dysfunction disease states.
It is yet another object of the invention to provide a novel pharmaceutical composition comprising purified plasma that includes concentrated levels of immununoglobulins.
It is still a further object of the invention to provide a novel pharmaceutical composition comprising purified plasma that is substantially free of IgA.
These and other objects of the invention will become apparent from the detailed description of the invention which follows.